Phylodynamics of Influenza A/H1N1pdm09 in India Reveals Circulation Patterns and Increased Selection for Clade 6b Residues and Other High Mortality Mutants

Abstract

The clinical severity and observed case fatality ratio of influenza A/H1N1pdm09 in India, particularly in 2015 and 2017 far exceeds current global estimates. Reasons for these frequent and severe epidemic waves remain unclear. We used Bayesian phylodynamic methods to uncover possible genetic explanations for this, while also identifying the transmission dynamics of A/H1N1pdm09 between 2009 and 2017 to inform future public health interventions. We reveal a disproportionate selection at haemagglutinin residue positions associated with increased morbidity and mortality in India such as position 222 and clade 6B characteristic residues, relative to equivalent isolates circulating globally. We also identify for the first time, increased selection at position 186 as potentially explaining the severity of recent A/H1N1pdm09 epidemics in India. We reveal national routes of A/H1N1pdm09 transmission, identifying Maharashtra as the most important state for the spread throughout India, while quantifying climactic, ecological, and transport factors as drivers of within-country transmission. Together these results have important implications for future A/H1N1pdm09 surveillance and control within India, but also for epidemic and pandemic risk prediction around the world.

Keywords: India; Influenza; phylogenetics; public health.

Figure 1

(a) Bayesian Skygrid estimation of effective viral population size (N_e) of A/H1N1pdm09 in India between 2009 and 2017. Here, we show the mean N_e and respective 95% Bayesian credible interval (BCI) plotted in blue. (b) Official A/H1N1pdm09 case and death counts (left axis) reported by the National Centre for Disease Control in Delhi (NCDC) [15,16]. Calculated yearly case fatality ratios (CFR) with corresponding percentages shown (right axis). The arrow in Figure 1a points to the inferred seasonal epidemic in 2013/14, in contrast to reported cases in Figure 1b.

Figure 2

Relative structural locations of A/H1N1pdm09 residues within the HA monomer under positive selection in India. Sites under selection are highlighted in red and numbered without signal peptide (H1 numbering). Letters in parentheses indicate sites located within the known antigenic domains of HA1. (RCSB PDB ID: 4LXV).

Figure 3

Phylogeography of definitive A/H1N1pdm09 transmission between S/UT in India since 2009. Paths between S/UT are coloured by inferred transmission time and directions indicated by adjacent arrows. All routes shown are characterised by definitive statistical support (Bayes factor (BF) > 100). Supported to very strongly supported routes (100 > BF > 3) are not shown but can be seen in Supplementary Table S8.